Using a Silver Lipidocolloid Dressing in the Treatment of Leg Ulcers at Risk for Secondary Infection: A Randomized Controlled Study

The vast majority of chronic wounds are colonized by different microorganisms and contain biofilms; the probability of their healing properly is limited when the bacterial load exceeds a certain level of contamination.^1,2 Highly effective, wound-compatible antimicrobial agents and the spread of multidrug-resistant organisms has led to the use of wound antiseptics in the treatment of locally infected or critically colonized wounds; systemic antibiotherapy remains a requirement when the infection spreads.³

Among available antiseptics, topical silver has a long tradition in wound management due to its broad antimicrobial effect against both gram-positive and gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, as well as some fungi, viruses, and protozoa.⁴ Silver in its ionic form (Ag+) is transported into the cell and disrupts numerous cell functions by binding to proteins and interfering with energy production, enzyme function, and cell replication.⁵ With these diverse abilities, silver has been only rarely described as causing resistance; resistance is rather unlikely and clinically irrelevant.⁶ Interestingly, depending on the product and the condition of the wound, the silver concentration in the wound dressing, and the silver ions locally available, a pronounced variability due to the heterogeneity of the products has been noted when considering clinical outcomes.⁷

After a lipidocolloid healing matrix (TLC matrix — UrgoTul Dressing, URGO Medical, Fort Worth, TX) was developed and assessed in acute and chronic noninfected wounds with a high level of clinical evidence,⁸ silver sulfate (3.5%) was added to provide an appropriate alternative for the management of wounds with clinical signs of infection (ie, pain between dressing changes, perilesional skin erythema, edema, offensive odor, and heavy exudate). The efficacy of this silver lipidocolloid matrix (UrgoTul Ag/Silver) was reported in vitro as having the ability to destroy S aureus and Pseudomonas aeruginosa biofilms and to have antimicrobial effects on numerous microorganisms^9,10 and in vivo to have significant anti-inflammatory effects on chronic skin inflammation induced on the backs of hairless mice.¹¹

A multicenter pilot clinical trial was performed to assess the efficacy of the silver lipidocolloid dressing under compression bandaging in 45 patients with a venous leg ulcer (VLU) presenting clinical signs of critical colonization¹²; the positive clinical outcomes included reduction of wound surface area and a decrease in clinical signs of infection at week 4. However, the noncomparative design of the study limited the consistency of the results.

The aim of this randomized clinical study was to evaluate the benefits (efficacy, tolerance, and acceptability) of UrgoTul Silver dressing when used in VLUs presenting clinical signs of infection.

A multicenter, open-label, randomized controlled clinical trial was conducted in 2-arm parallel groups in 24 French investigating centers (hospital dermatology and vascular medicine departments)  and private practice dermatologists and angiologists after securing the approval of the Medical Ethics Committee of Versailles (France).

Participants. Patients with a leg ulcer presenting a high risk of secondary infection were treated with either the tested sequential strategy combining the use of UrgoTul Silver lipidocolloid dressing for the first 4-week period, then UrgoTul lipidocolloid dressing for the following 4 weeks; or with a control strategy based on the use of UrgoTul dressing without silver for the entire 8-week period. The investigators, all experts in VLU management, followed the mandatory protocol of compression therapy (one of their selection criteria for the trial) to which they added the dressings studied.

To be included in the trial, adult patients (ie, older than 18 years of age) agreed to wear compression bandages every day in combination with the trial dressings. Ulcers on the selected leg (ankle-brachial pressure index >0.8) had to demonstrate at least 3 of the 5 clinical signs of infection, a wound surface area between 5 cm²  and 40 cm², and an ulcer duration of a minimum of 6 weeks and less than 24 months. Patients receiving local or systemic antibiotics in the week before study inclusion and/or with clinically infected wounds or erysipelas, malignant wounds, recent deep venous thrombosis, and/or progressive neoplastic lesions treated by radiotherapy, chemotherapy, and/or immunosuppressive agents were excluded.

Evaluated treatments. The study dressing (UrgoTul Silver) is a nonadhesive, nonocclusive dressing made of nonwoven polyester mesh impregnated with hydrocolloid particles dispersed in a petroleum jelly matrix into which silver sulfate was incorporated and released as a silver ion when the dressing is in contact with the wound fluids. The control lipidocolloid dressing (UrgoTul) has characteristics similar to the study dressing; the only difference is the absence of the silver salts. Numerous clinical trials have demonstrated the benefits of this dressing in the local treatment of acute and chronic wounds.⁸

Protocol. Once written informed consent was obtained and the patient selection criteria validated, study participants were seen on a weekly basis for up to 4 weeks of treatment, then every 2 weeks until the eighth week of treatment. Per protocol, a clinical evaluation of the wound (assessment of fibrinous tissue, granulation tissue, condition of perilesional skin) including planimetric and photographic records, was performed at each planned visit. Pain (ie, the painful/painless nature of dressing changes, pain experienced between 2 dressing changes), ease of dressing application and removal, odor, maceration, and exudate leakage were evaluated in a qualitative manner.

The primary endpoint of the study was to assess the efficacy of these 2 dressings based on changes in wound surface area after 8 weeks of treatment. Secondary endpoints included changes in the baseline Clinical Score (based on the presence or absence of each of the 5 baseline selected clinical signs at each planned evaluation) and the clinical and biological safety of the trial product (occurrence of local adverse events for the clinical safety and through blood assays to ensure systemic passage of the silver for the biological safety), noted at baseline, week 4, and week 8. Blood silver level was assessed using electrothermal atomic absorption spectrometry (ET-AAS; Perkin Elmer 4100 ZL AAS; Perkin Elmer Inc, Waltham, MA) and product acceptability (ie, ease of application and removal, conformability, pain, bleeding at removal, maceration, dressing adherence to the wound, and dressing conformability, assessed on a qualitative scale [very poor, poor, good, very good]) by the nursing staff and the patients at each nursing visit.

Data analysis. A sample size of 96 patients was determined a priori by the statistician (independent from the sponsor) to demonstrate the superiority hypothesis of the study versus the control approach (80% power, alpha risk 5%). The efficacy analysis was conducted on an intention-to-treat (ITT) basis and included all randomized patients who received at least 1 care visit with 1 of the trial treatments and who underwent at least 1 posttreatment evaluation. Statistical analysis was conducted by an independent company in accordance with the plan designed and approved by the different parties involved in the trial. Data analysis was conducted using SAS/FSP (version 6.12)  Windows 2000 software (Microsoft, Redmond, WA). If a patient withdrew before the eighth week of the study, the efficacy analysis took into account the last evaluation available (last observation carried forward). The treated groups were compared using the Student’s t test or the nonparametric Wilcoxon test for continuous variables and chi-squared test for categorical variables. All analyses were conducted on the ITT population defined as all randomized patients with at least 1 follow-up planimetry value.

Population and pathology data at baseline. Of the 102 hospitalized patients or outpatients experiencing a leg ulcer considered at risk of secondary infection recruited into this clinical trial, 52 comprised the silver group and 50 the control group. The included population was predominantly composed of outpatients (72, 70.6%), female (71, 69.6%), markedly overweight (mean body mass index [BMI] 28.7), and had diabetes mellitus (19, 18.6%) and a history of deep venous thrombosis (33, 32.4%).

This clinical trial was the accumulation of 4796 days of treatment and documented 800 medical evaluations and 2461 local care operations. The median treatment time for each patient was 56 days and 51 days in the silver and control groups, respectively. Time between 2 dressing changes was similar (2.12 days vs. 1.84 days in the silver and control groups, respectively).

At baseline, wounds in both groups had a large surface area (average of 20 cm²); mean surface area was 22.3 cm² (range 3.11–119.90 cm²) and 17.5 (range 4.89–73.49 cm²) for the silver and nonsilver groups, respectively (P = .84). Wounds were of long duration (average 10.8 months); mean duration was 11.0 (range 3.11–119.90)  months and 10.5 months (range 4.89– 73.49) months for the silver and nonsilver groups, respectively (P = .11). Sixty-six (66) wounds (64.7%) were recurrent and had a wound bed covered by ~50% of sloughy tissue, with healthy perilesional skin present in only 3 patients. In total, investigators considered 81 (79.4%) of the wounds stagnant or worsening despite appropriate wound bed preparation and provision of specialized services by vascular or dermatology physicians, no necrosis after wound debridement, and provision of compression therapy (provided to more than 86% of the treated wounds at baseline before the start of the trial).

No significant differences were noted between the 2 groups for all the evaluated parameters (ie, demographic and wound data such as age, gender, weight, BMI, medical and surgical history, wound area, wound duration, wound recurrence, and condition of the perilesional skin), except for the Clinical Score, which was significantly higher in the silver than in the control group (3.84 vs. 3.40; P = .0032), due to a higher number of existing clinical signs of infection in the silver group (see Table 1). Of note: at least 3 of the 5 selected clinical signs were mandatory to include the patient in this RCT.

Comparative findings.
Efficacy. In terms of the primary endpoint, at week 4 with more than 95% of the patients complying with their venous compression treatment, the median surface area decreased 4.2 cm² (29.1%) vs. 1.1 cm² (9.5%) in the silver and control groups, respectively (P = .023). After week 4, when all patients in the silver group switched to the nonsilver-containing contact layer, ulcer area continued to decrease while no clinically relevant change was observed in the control group. At week 8, the median absolute wound surface reduction was 5.9 cm² and 0.8 cm², respectively, in the silver and nonsilver groups (P = .002). The same trends were observed when surface area changes were expressed as percentage reduction from baseline. After 8 weeks of treatment, relative median wound area decreased 47.9% in the silver group versus 5.6% in the control group (P = .036) (see Figure).  

Hence, wound closure was significantly faster by week 4 in the silver group (median 0.145 cm²/day vs. 0.044 cm²/day; P = .009); even after switching to the nonsilver dressing, this parameter remained unchanged between week 4 and week 8, remaining significantly higher in the sequential group (0.135 cm²/day vs. 0.023 cm²/day; P = .001).

Regression analyses in a model that included ulcer outcome prediction factors (age, BMI, ulcer duration, area at inclusion, and recurrence) showed the likelihood of reaching an ulcer area regression of 40% in 8 weeks was 2.7 times greater in the silver group than in the control group (OR: 2.7; 95% confidence interval: 1.1-6.7; P = .038). None of the other factors included in the model was significant.

In terms of the secondary endpoints, at the end of the 8-week treatment period, the Clinical Score (based on the presence of the 5 predetermined clinical signs of infection) was significantly lower in the silver group than in the control group (1.43 vs. 2.31, respectively; P = .0001). At week 4, the percentage of ulcers with no predetermined clinical signs (clinical score equal to zero) was significantly higher in the silver than in the control group (39.2% vs. 16.7%; P = .0097) and remained significant at week 8 (35.3% vs. 20.8%; P = .044).

Safety. A total of 22 local adverse events (11 in each treatment group and not different between the 2 groups in their nature and frequency), possibly related to the tested dressings, were reported in 20 patients. In the first period (day 0 to week 4), no secondary infection occurred in the silver group; 2 infections were noted in the control group.

At the end of the treatment period, the perilesional skin was considered healthy in more cases in the silver group than in the control group (20 vs. 9 patients, 39.2% vs. 18.8%, in the silver and control groups, respectively), compared to the 3 patients with healthy perilesional skin at baseline.
Assays of blood silver (at day 0, week 4, and week 8) performed in the silver group to document biological safety showed the silver dressing did not increase blood silver levels. In addition, no local perilesional signs (which could evoke an argyria) or general signs (which could suggest a toxicity of silver salts) occurred during the trial.

Acceptability. Because the study was sequential for the silver arm, the acceptability results were divided into 2 periods. In the first period (day 0 to week 4), the silver dressing was significantly superior in terms of easier dressing removal (P = .03), less pain (P <.001), and less bleeding at removal (P = .001); no significant differences were observed between the 2 treatment groups in terms of maceration, dressing adherence to the wound, ease of application, and dressing conformability. In the second period (week 4 to week 8), no significant difference between the 2 groups was noted in the parameters studied.

The benefits and good safety profile (clinical and biological) of the silver dressing documented in this clinical trial are widely supported by clinical data from real-life surveys performed in European countries among thousands of patients with acute or chronic wounds presenting local signs of infection.¹³ Following treatment with lipidocolloid silver dressings, 30% of the wounds healed, while the mean number of signs of local infection decreased from 4.0 to 0.54. According to physicians, 70% of the wounds were “definitely not infected” at the end of the treatment period, 47% improved, and 20% showed no additional signs of devitalized tissue. Almost all (97%) of the participants rated dressing tolerability as good/very good.

The high level of evidence of the current RCT lived up to the strong expectations of the French Health Care Authorities,¹⁴ allowing the lipidocolloid silver dressings to be reimbursed today in France, unlike all other existing silver dressings (hydrofibers, foams, or contact layers).¹⁵

A randomized clinical study found the use of UrgoTul Silver lipidocolloid dressing for a short period of time (4 weeks maximum) can restart the healing process in venous ulcers presenting clinical signs of infection. The ability of the dressing’s silver ions to control a high bacterial load and to provide anti-inflammatory properties appears to promote a favorable microenvironment and foster a sustained decrease of the wound surface area of the chronic wounds presenting a high risk of infection.